The long-term objective of this application is to improve the pharmacotherapy of autism by developing safer and more efficacious novel drug treatment strategies. Autism is a major public health concern in the U.S. and throughout the world. The cost of the disability is estimated to be in the range of $30 billion annually in the U.S. alone. Despite an improved ability to reduce the aggression, self-injurious behavior (SlB) and irritability that often occur with autism, existing drug treatments are associated with significant adverse effects. These include extrapyramidal symptoms (EPS) and tardive dyskinesia with "typical antipsychotics" and significant weight gain and associated hyperlipidemia, hypertriglyceridemia, diabetes mellitus, hepatic abnormalities, and at times mortality with the "atypical" antipsychotics. The only atypical antipsychotic not linked with significant weight gain, ziprasidone, has been shown to prolong the corrected QT interval on electrocardiogram (ECG); a potentially fatal complication. Both typical and atypical antipsychotics cause hyperprolactinemia. Furthermore, to date, no drug treatment has been developed for the core social impairment of autism. In this application, Study A. Phase I involves an 8-week randomized double blind, placebo-controlled trial of the novel antipsychotic aripiprazole for the short-term treatment of aggression, SlB and irritability in children and adolescents (age 6-17 years) with autism (n=88). Subjects who respond will be eligible to enter a 4-month open-label continuation trial of aripiprazole (Study A. Phase II) designed to determine if ongoing treatment is associated with the maintenance of response. Potential adverse effects of aripiprazole, with particular attention to EPS, weight gain, prolongation of the corrected QT interval on ECG, and hyperprolactinemia, will be monitored throughout both Phases of Study A. Study B. is a pilot combination drug treatment study to determine if adding open-label D-cycloserine, a partial agonist at the N-methyI-D-aspartate (NMDA) subtype of glutamate receptor, to on-going open-label aripiprazole results in improved social behavior in subjects whose aggression, SlB and irritability Iremain stabilized upon completion of Study A. Phase II (following 6 months of aripiprazole monotherapy).